What is the recommended diagnostic approach for cystic fibrosis, including newborn screening, sweat chloride testing, and CFTR genetic analysis?

Diagnosing Cystic Fibrosis

The diagnosis of cystic fibrosis requires BOTH clinical features (chronic respiratory symptoms, pancreatic insufficiency, positive family history, or positive newborn screening) AND objective evidence of CFTR dysfunction through sweat chloride testing ≥60 mmol/L or identification of two CF-causing mutations on genetic testing. 1

Newborn Screening Approach

Newborn screening is the standard of modern CF care and should be performed in all newborns, but it is NOT diagnostic—confirmatory testing is mandatory. 1, 2

• Screening uses immunoreactive trypsinogen (IRT) as the initial test, with algorithms varying by region using either IRT/repeat IRT or IRT/DNA mutation analysis 1
• IRT can be falsely elevated due to prematurity, stressful delivery, or CF carrier status, and screening has a sensitivity of only 93-98%, missing 2-7% of CF cases 3
• All positive newborn screens require confirmatory sweat chloride testing before diagnosis can be made 1

Sweat Chloride Testing: The Gold Standard

Sweat chloride testing remains the cornerstone diagnostic test and must be performed according to standardized protocols. 4

Timing and Technical Requirements:

• Perform bilaterally when infant weighs >2 kg and is at least 36 weeks corrected gestational age 4, 1
• Test as soon as possible after 10 days of age, ideally by end of neonatal period (4 weeks) 4, 1
• Analysis must be performed within a few hours of sweat collection 4, 1
• Infants <2 weeks old or <2 kg often cannot produce sufficient sweat for reliable testing 1

Interpretation:

• ≥60 mmol/L = Diagnostic for CF when patient has clinical features, positive family history, or positive newborn screen 4, 1
• 30-59 mmol/L = Intermediate/ambiguous range requiring repeat testing on two separate occasions and extended CFTR genetic analysis 4, 1
• <30 mmol/L = CF unlikely, but may still be considered if evolving clinical criteria and CFTR genotyping support CF 4

Critical pitfall: Infants with CF often initially present with values in the intermediate range (30-59 mmol/L), which may increase over time—do not dismiss intermediate values without extended genetic testing and follow-up. 1, 5

CFTR Genetic Testing

CFTR genetic testing via blood test or cheek swab should be performed to identify disease-causing mutations, with identification of two CF-causing mutations confirming diagnosis regardless of sweat test results. 1

• More than 2000 CFTR variants have been described, not all of which cause CF 4, 6
• For individuals with CRMS/CFSPID (screen-positive, inconclusive diagnosis) who have <2 disease-causing variants identified by newborn screening, CFTR sequencing including intronic regions should be performed 1
• Genetic testing is particularly important for intermediate sweat chloride values and atypical presentations 7

Clinical Features That Trigger Diagnostic Evaluation

Do not rely solely on newborn screening when clinical suspicion exists—actively pursue diagnosis in symptomatic patients. 3

Red flag symptoms requiring immediate CF evaluation:

• Persistent or recurrent cough with frequent respiratory infections 8
• Bulky, foul-smelling stools (present in >80% at diagnosis, indicating pancreatic insufficiency) 3, 8
• Poor weight gain or failure to thrive 8
• Excessive sweating or salty-tasting sweat 3, 8
• Male infertility (congenital absence of vas deferens) 7
• Recurrent pancreatitis or nasal polyposis 2

Advanced Testing for Inconclusive Cases

When sweat testing and genetic analysis cannot confirm or exclude CF, in vivo demonstration of abnormal ion transport across nasal epithelium can serve as diagnostic evidence. 1, 7

• Transepithelial nasal potential difference measurements can support difficult diagnoses 2, 7
• This is particularly relevant for adults with milder forms presenting later in life 7

Management During Diagnostic Workup

Treatment should not be delayed while establishing diagnosis in infants with presumptive CF identified through newborn screening. 4

• Initiate pancreatic enzyme replacement and fat-soluble vitamin supplements immediately in symptomatic infants 3
• Start high-fat diet and establish aggressive monitoring for respiratory infections 3
• Early diagnosis and treatment significantly reduce morbidity and mortality compared to symptom-based diagnosis 3

Follow-Up for Inconclusive Cases (CRMS/CFSPID)

Patients with CRMS/CFSPID require continued follow-up at specialized CF centers with repeat sweat chloride testing beyond age 1 year. 5

• Monitor at 6 months and annually until age 8 years 8
• Perform selective respiratory cultures (Pseudomonas aeruginosa, Staphylococcus aureus) 8
• Some patients initially classified as CRMS will eventually meet diagnostic criteria for CF 5